A phase II study of durvalumab and stereotactic ablative body radiotherapy (SABR) in locally advanced pancreatic adenocarcinoma (LA PDAC).
Authors: Fergus Keane, Joshua David Schoenfeld, Fionnuala Crowley, Catherine Anne O'Connor, Charlie White, Carly Schwartz, Robin Brenner, Mary Larsen, Wungki Park, Anna M. Varghese, Kenneth H. Yu, Jia Li, Alice Zervoudakis, Zoe Goldberg, Joanne F. Chou, Santosha Vardhana, Marsha Reyngold, Christopher H Crane, Richard Tuli, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2023)

725 Background: Immune checkpoint blockade (ICB) has a modest signal in the treatment of patients with genomically unselected pancreatic cancer (PDAC). Synergistic effects of combined radiotherapy and ICB are postulated. Preliminary results of a phase 1/2 trial of anti-PD-L1 antibody durvalumab (D) and SABR in locally advanced (LA) and borderline resectable PDAC (Tuli, AACR; 2019; Abstr B58), noted SABR and D to be safe and tolerable following induction chemotherapy. We sought to further evaluate the tolerability and efficacy of D and SABR, in LA PDAC. Methods: A single-arm, open-label phase 2 trial was conducted at Memorial Sloan Kettering (MSK). Key eligibility: histologically confirmed LA unresectable PDAC, with stable or responding disease following 4-6 months (m) of FOLFIRINOX (FFX), ECOG 0-2. Therapy: D and SABR; D dosed on day 1 750mg x 4 doses Q14 days, and subsequently 1500mg Q 28 days x 11 doses (1 year total), or until progression of disease (POD), or limiting toxicity. All patients received MRI adaptive ablative radiation, 50Gy in 5 fractions between doses 1 and 2 of D. Primary endpoint: 6-m progression free survival (6 m PFS) by RECIST v1.1. Secondary endpoints were Duration of Response, Overall Response Rate (ORR), CA 19-9 response, rates of downstaging/resection, and survival outcomes (overall survival (OS) and progression-free survival (PFS)) calculated from date of enrolment. OS and PFS were estimated using Kaplan-Meier method. Pre- and on-treatment tissue, blood and microbiome samples were collected to evaluate tumor-intrinsic and peripheral immunogenomic correlates of response. Results: Between 09/2020 and 05/2022, N = 18 enrolled. Median age 67.5 years (IQR; 62.5, 71.5), 28% (5/18) female. Baseline Performance Status: N = 8 (44%) ECOG 0; N = 10 (56%) ECOG 1. Tumor location: Head/uncinate N = 9 (50%), body N = 7 (39%), neck N = 2 (11%). Median # doses FFX prior to enrolment: 8.5 (IQR; 8.0- 11.0). At median follow-up of 13.8 m, 6-m PFS: 62% (95% CI 43%, 91%). Median PFS: 10.2 m (95% CI; 5.03, NA) and median OS 17.2 m (95% CI; 12.98, NA). Disease progression (any time) N = 12, of which local POD in N = 7 (58%). N = 3 completed maintenance D; N = 5 on active treatment. ORR: N = 17 (94.4%) stable disease (95% CI; 64.6%, 99.4%). Toxicity endpoints of special interest: Grade 3 ICB-related: in N = 4 patients; diarrhea N = 2; elevated AST/ALT N = 2; G3 lipase elevation N = 1; attribution uncertain. Conclusions: D and SABR following FFX in LA PDAC had an encouraging 6-m PFS of 62% (43-91%) and a tolerable safety profile. Immuno-genomic analyses of correlative biospecimens is underway. Funding support AstraZeneca. Clinical trial information: NCT03245541 .